Molecular and Cellular Impact of Inflammatory Extracellular Vesicles (EVs) Derived from M1 and M2 Macrophages on Neural Action Potentials.
Several factors can contribute to neuroinflammatory disorders, such as cytokine and chemokines that are produced and released from peripherally derived immune cells or from locally activated cells such as microglia and perivascular macrophages in the brain. The primary function of these cells is to clear inflammation; however, following inflammation, circulating monocytes are recruited to the central nervous system (CNS). Monocyte-derived macrophages in the CNS play pivotal roles in mediating neuroinflammatory responses. Macrophages are heterogeneous both in normal and in pathological conditions due to their plasticity, and they are classified in two main subsets, classically activated (M1) or alternatively activated (M2). There is accumulating evidence suggesting that extracellular vesicles (EVs) released from activated immune cells may play crucial roles in mediating inflammation. However, a possible role of EVs released from immune cells such as M1 and M2 macrophages on neuronal functions in the brain is not known. In order to investigate the molecular and cellular impacts of macrophages and EVs released from macrophage subtypes on neuronal functions, we used a recently established in vitro M1 and M2 macrophage culture model and isolated and characterized EVs from these macrophage subtypes, treated primary neurons with M1 or M2 EVs, and analyzed the extracellular action potentials of neurons with microelectrode array studies (MEA). Our results introduce evidence on the interfering role of inflammatory EVs released from macrophages in interneuronal signal transmission processes, with implications in the pathogenesis of neuroinflammatory diseases induced by a variety of inflammatory insults.


Medical consequences of marijuana use: a review of current literature.
With the advent of legalization of marijuana for medicinal and recreational purposes, and the increase use of marijuana, healthcare providers will be increasingly confronted with marijuana users as patients in clinical environments. While there is vast literature regarding the societal and mental health harms associated with marijuana use, there is a paucity of reviews of the potential consequences of marijuana use on physical health or medical conditions. We examine the recent literature on the physical harms associated with illicit and legal marijuana administration. We surveyed the peer-reviewed medical literature from 1998 to 2013 of studies assessing the association of marijuana use and physical diseases. We conclude that healthcare providers should be cognizant that the existing literature suggests that marijuana use can cause physical harm. However, evidence is needed, and further research should be considered, to prove causal associations of marijuana with many physical health conditions.


Acylation-coupled lipophilic induction of polarisation (Acyl-cLIP): a universal assay for lipid transferase and hydrolase enzymes.
Posttranslational attachment of lipids to proteins is important for many cellular functions, and the enzymes responsible for these modifications are implicated in many diseases, from cancer to neurodegeneration. Lipid transferases and hydrolases are increasingly tractable therapeutic targets, but present unique challenges for high-throughput biochemical enzyme assays which hinder development of new inhibitors. We present Acylation-coupled Lipophilic Induction of Polarisation (Acyl-cLIP) as the first universally applicable biochemical lipidation assay, exploiting the hydrophobic nature of lipidated peptides to drive a polarised fluorescence readout. Acyl-cLIP allows sensitive, accurate, real-time measurement of S- or N-palmitoylation, N-myristoylation, S-farnesylation or S-geranylgeranylation. Furthermore, it is applicable to transfer and hydrolysis reactions, and we demonstrate its extension to a high-throughput screening format. We anticipate that Acyl-cLIP will greatly expedite future drug discovery efforts against these challenging targets.


Inhibition of ischemia-induced phospholipase activation by quinacrine protects jeopardized myocardium in rats with coronary artery occlusion.
Phospholipase activation has been proposed as one relevant biochemical step toward irreversible myocardial injury during ischemia. Accordingly, after coronary artery occlusion, the time course of myocardial phospholipid degradation was studied in 83 control rats and 84 rats treated with quinacrine (75 mg/kg s.c. every 8 hr), a phospholipase inhibitor. Animals were sacrificed at different times ranging from 2 to 48 hr postocclusion. In controls a rapid fall in left ventricular phospholipid concentration (from 1.33 +/- 0.12 to 0.67 +/- 0.05 micrograms of P/mg of protein) and creatinkinase (CK) activity (from 9.84 +/- 0.49 to 6.93 +/- 0.60 I.U./mg of protein) was observed within 4 hr postocclusion. In quinacrine-treated animals phospholipids and CK also fell initially; however, 24 and 48 hr after occlusion they were higher than in controls (phospholipids: 0.99 +/- 0.05 vs. 0.62 +/- 0.04 micrograms of P/mg of protein, P less than .001; CK: 7.76 +/- 0.54 vs. 4.99 +/- 0.37 I.U./mg of protein, P less than .001, at 48 hr). Additional rats surviving coronary occlusion were divided randomly into a control (n = 14) and three treated groups receiving quinacrine every 8 hr at the dose of 5 (n = 13), 20 (n = 13) or 75 mg/kg (n = 15); 13 rats were sham-operated. Forty-eight hours postocclusion myocardial phospholipids were measured and infarct size calculated by CK depletion. Infarct size was significantly smaller in high dose quinacrine-treated than in control rats (16.6 +/- 5.7 vs. 42.1 +/- 4.4% of left ventricle, P less than .001). In treated animals, myocardial phospholipid concentration was also significantly higher.(ABSTRACT TRUNCATED AT 250 WORDS)


Pediatric low-grade ganglioglioma: epidemiology, treatments, and outcome analysis on 348 children from the surveillance, epidemiology, and end results database.
Low-grade gangliogliomas/gangliocytomas (GGs) are rare tumors of the central nervous system that occur mostly in young people. Because of their rarity, large-scale, population-based studies focusing on epidemiology and outcomes are lacking. To use the Surveillance, Epidemiology, and End Results (SEER) data sets of the National Cancer Institute to study demographics, tumor location, initial treatment, and outcome data on low-grade GGs in children. SEER-STAT v8.1.2 identified all patients aged 0 to 19 years in the SEER data sets with low-grade GGs. Using the Kaplan-Meier method and Cox proportional hazard regression, we examined associations between these characteristics and survival. There were 348 children with low-grade GGs diagnosed from 2004 to 2010, with a median follow-up of 37 months. Tumors were more prevalent in males (n = 208, 59.8%) than females (n = 140, 40.2%) (P < .001). Almost 63% occurred in children >10 years, whereas only 3.5% were found in those <1 year old. Approximately 50% were located in the temporal lobes, and only 3.7% and 3.5% were located in the brainstem and spinal cord, respectively. Surgery was performed on 91.6% of cases, with gross total resection achieved in 68.3%. Radiation was used in 3.2%. Young age (<1 year) and brainstem location were associated with worse overall survival. This study shows that low-grade GGs occur in older children with a male preference. Gross total resection is achieved in the majority of cases, and radiation is rarely used. Although the majority of patients have an excellent prognosis, infants and patients with brainstem tumors have worse survival rates.


Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity.
One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.


Recent advances in liver resection for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The association of HCC with chronic liver disease (CLD) is well known and making treatment complex and challenging. The treatment of HCC must take into consideration, the severity of CLD, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC. Better liver function assessment, increased understanding of segmental liver anatomy using more accurate imaging studies, and surgical technical progress are the important factors that have led to reduced mortality, with an expected 5 year survival of 38-61% depending on the stage of the disease. However, the procedure is applicable to <30% of all HCC patients, and 80% of the patients after LR recurred within 5 years. There are recent advances and prospects in LR for HCC in several aspects. Three-dimensional computed tomography imaging assisted preoperative surgical planning facilitates unconventional types of LR. Emerging evidences of laparoscopic hepatectomy and prospects for the use of newly developing chemotherapies as a combined therapy may lead to expanding indication of LR. LR and liver transplantation could be associated rather than considered separately with the current concepts of "bridging LR" and "salvage transplantation."


Effects of the generation of single-stranded DNA on the maintenance of plasmid pMV158 and derivatives in Lactococcus lactis.
The effects of the single-strand origins (SSOs) of the broad-host-range streptococcal plasmid pMV158 on (i) the conversion of its single-stranded (ss) DNA replication intermediates to double-stranded (ds) plasmid DNA and (ii) its maintenance were analyzed. pMV158 is distinguished from most other plasmids that replicate by the rolling-circle mechanism by the presence of two single-strand origins of replication, palA and palU. In this paper the results obtained with Lactococcus lactis are presented; complementary studies with Bacillus subtilis are presented in the accompanying paper (Meijer et al., 1995). In the presence of both SSOs, no ss plasmid DNA was observed in L. lactis. The removal of either palA or palU resulted in the appearance of low amounts of ssDNA. High amounts of ssDNA were detected, however, when both SSOs were deleted. The results indicated that both SSOs were active, albeit that palU was the most effective of the two. In the presence of both SSOs, the plasmid was stably maintained in L. lactis under nonselective growth conditions. Also, the derivatives containing only one of the two SSOs were maintained rather stably. In contrast, the derivative devoid of both SSOs was poorly maintained. It was concluded that, in the absence of a functional SSO, the generation of large amounts of ssDNA drastically reduces the maintenance of pMV158 in L. lactis. The results also showed that the presence of the plasmid-located mob gene, required for conjugative mobilization, was involved neither in the accumulation of ssDNA nor in the maintenance of pMV158.


Prioritizing key resilience indicators to support coral reef management in a changing climate.
Managing coral reefs for resilience to climate change is a popular concept but has been difficult to implement because the empirical scientific evidence has either not been evaluated or is sometimes unsupportive of theory, which leads to uncertainty when considering methods and identifying priority reefs. We asked experts and reviewed the scientific literature for guidance on the multiple physical and biological factors that affect the ability of coral reefs to resist and recover from climate disturbance. Eleven key factors to inform decisions based on scaling scientific evidence and the achievability of quantifying the factors were identified. Factors important to resistance and recovery, which are important components of resilience, were not strongly related, and should be assessed independently. The abundance of resistant (heat-tolerant) coral species and past temperature variability were perceived to provide the greatest resistance to climate change, while coral recruitment rates, and macroalgae abundance were most influential in the recovery process. Based on the 11 key factors, we tested an evidence-based framework for climate change resilience in an Indonesian marine protected area. The results suggest our evidence-weighted framework improved upon existing un-weighted methods in terms of characterizing resilience and distinguishing priority sites. The evaluation supports the concept that, despite high ecological complexity, relatively few strong variables can be important in influencing ecosystem dynamics. This is the first rigorous assessment of factors promoting coral reef resilience based on their perceived importance, empirical evidence, and feasibility of measurement. There were few differences between scientists' perceptions of factor importance and the scientific evidence found in journal publications but more before and after impact studies will be required to fully test the validity of all the factors. The methods here will increase the feasibility and defensibility of including key resilience metrics in evaluations of coral reefs, as well as reduce costs. Adaptation, marine protected areas, priority setting, resistance, recovery.


Stem Cells in Skin Wound Healing: Are We There Yet?
Significance: Cutaneous wound healing is a serious problem worldwide that affects patients with various wound types, resulting from burns, traumatic injuries, and diabetes. Despite the wide range of clinically available skin substitutes and the different therapeutic alternatives, delayed healing and scarring are often observed. Recent Advances: Stem cells have arisen as powerful tools to improve skin wound healing, due to features such as effective secretome, self-renewal, low immunogenicity, and differentiation capacity. They represent potentially readily available biological material that can particularly target distinct wound-healing phases. In this context, mesenchymal stem cells have been shown to promote cell migration, angiogenesis, and a possible regenerative rather than fibrotic microenvironment at the wound site, mainly through paracrine signaling with the surrounding cells/tissues. Critical Issues: Despite the current insights, there are still major hurdles to be overcome to achieve effective therapeutic effects. Limited engraftment and survival at the wound site are still major concerns, and alternative approaches to maximize stem cell potential are a major demand. Future Directions: This review emphasizes two main strategies that have been explored in this context. These comprise the exploration of hypoxic conditions to modulate stem cell secretome, and the use of adipose tissue stromal vascular fraction as a source of multiple cells, including stem cells and factors requiring minimal manipulation. Nonetheless, the attainment of these approaches to target successfully skin regeneration will be only evident after a significant number of in vivo works in relevant pre-clinical models.


Tax policy, adult binge drinking, and youth alcohol consumption in the United States.
Prior research attributed youth alcohol consumption to the attitudes and drinking patterns among adults. Yet at a population level, few have examined the relationship between state-level adult binge drinking prevalence and youth drinking behaviors, or whether tax policy plays a role in this relationship. We analyzed 6 biennial surveys (1999 to 2009) of individual-level youth alcohol use and related behaviors from state-based Youth Risk Behavior Surveys and corresponding years of state-level adult binge drinking prevalence from the Behavioral Risk Factor Surveillance System. We employed logistic regression with generalized estimating equations method to assess the extent to which state adult binge drinking predicted individual-level youth drinking outcomes and examined the role of alcohol taxes in that relationship. Population-aggregate analyses based on 194 state-year strata showed a positive correlation between state adult binge drinking and youth binge drinking (Pearson r = 0.40, p < 0.01). For individual-level youth drinking outcomes, a 5 percentage point increase in binge drinking prevalence among adults was associated with a 12% relative increase in the odds of alcohol use (adjusted OR = 1.12, 95% CI: 1.08, 1.16). Taxes were strongly inversely related with adult and youth drinking measures, and the effect of tax on youth drinking was attenuated after controlling for adult binge drinking. Both tax and adult binge drinking are strong predictors of youth drinking. Tax may affect youth drinking through its effect on adult alcohol consumption. Implementing effective alcohol policies to reduce excessive drinking in the general population is an important strategy to reduce youth drinking.


Clinical epidemiology of HIV/AIDS in China from 2004-2011.
This study retrospectively analyzed Chinese publicly reported data on Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS). The HIV/AIDS morbidity (1/100,000) and mortality (1/100,000) rates in China continually increased from 0.23 and 0.06 in 2004 to 1.53 and 0.69 in 2011, respectively. The AIDS case fatality rate decreased yearly from 53.57% in 2008 to 45.11% in 2011, and the fatality rate in rural areas (0.25-0.42%) was higher than that in cities (0.13-0.22%). The number of HIV/AIDS patients discharged from city-level hospitals increased from 329 in 2004 to 7,266 in 2011, and this number was higher than the number of similar patients discharged from county-level (rural) hospitals (the number of HIV/AIDS patients increased from 252 in 2004 to 5,957 in 2011). The factors contributing to these trends include: enhanced physician HIV/AIDS education regarding diagnosis, intervention, monitoring, testing, and treatment; improved safety of blood collection and use; and improved management of HIV/AIDS patients. Therefore, HIV/AIDS prevention and control in rural areas of China is the key to reducing HIV transmission and mortality in China.


Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.
Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery.


The pharmacology of weight gain with antipsychotics.
In general, antipsychotic agents have diverse actions on a wide range of neurotransmitter systems. Data strongly suggest that a number of these systems may play a role in the regulation of body weight. In addition to having very distinct pharmacologic profiles, individual agents possess discrete weight gain liabilities. This article briefly reviews the evidence for the involvement of specific neurotransmitter systems in the control of body weight and describes the relevant pharmacologic characteristics of individual antipsychotic agents. By comparing the pharmacologic profiles of specific antipsychotic agents with their respective weight gain liabilities, this article attempts to gain an insight into the specific receptors underlying a drug's propensity to induce weight gain. However, there is still much to be learned concerning weight control mechanisms, and the role of many of the receptors at which antipsychotic agents are active remains unclear. In spite of this, an overview of current knowledge in the field may facilitate prediction of a potential novel antipsychotic agent's weight gain liability.


Effects of chitin synthesis inhibitor treatment on Lepeophtheirus salmonis (Copepoda, Caligidae) larvae.
The salmon louse (Lepeophtheirus salmonis) is an ectoparasite infecting Atlantic salmon (Salmo salar), which causes substantial problems to the salmon aquaculture and threatens wild salmon. Chitin synthesis inhibitors (CSIs) are used to control L. salmonis in aquaculture. CSIs act by interfering with chitin formation and molting. In the present study, we investigated the action of four CSIs: diflubenzuron (DFB), hexaflumuron (HX), lufenuron (LF), and teflubenzuron (TFB) on larval molt. As the mode of action of CSIs remains unknown, we selected key enzymes in chitin metabolism and investigated if CSI treatment influenced the transcriptional level of these genes. All four CSIs interfered with the nauplius II molt to copepodids in a dose-dependent manner. The EC50 values were 93.2 nM for diflubenzuron, 1.2 nM for hexaflumuron, 22.4 nM for lufenuron, and 11.7 nM for teflubenzuron. Of the investigated genes, only the transcriptional level of L. salmonis chitin synthase 1 decreased significantly in hexaflumuron and diflubenzuron-treated larvae. All the tested CSIs affected the molt of nauplius II L. salmonis larvae but at different concentrations. The larvae were most sensitive to hexaflumuron and less sensitive to diflubenzuron. None of the CSIs applied had a strong impact on the transcriptional level of chitin synthesis or chitinases genes in L. salmonis. Further research is necessary to get more knowledge of the nature of the inhibition of CSI and may require methods such as studies of protein structure and enzymological studies.


Rest and exercise hemodynamic and adrenergic responses to enalapril, hydrochlorothiazide, and combination treatment in patients with systemic hypertension.
The effects of enalapril (10-20 mg twice daily), hydrochlorothiazide (25-50 mg twice daily), and combination enalapril-hydrochlorothiazide therapy (10-20 mg enalapril/25-50 mg hydrochlorothiazide in combination tablet twice daily) were evaluated and compared to no therapy (control) in eight patients with mild to moderate hypertension at rest and during treadmill exercise. All active treatments reduced standing blood pressure in patients at rest compared to the control group (p less than 0.05); however, none produced significant reductions of standing blood pressure in patients at peak exercise. Standing heart rates of patients at rest and at peak exercise were not changed with active therapy. However, standing heart rate in patients at rest was lower with enalapril than with hydrochlorothiazide and combination therapy (p less than 0.05). Heart rate of patients on hydrochlorothiazide was higher than with control and other therapies at Stage I of exercise (p less than 0.01). Supine norepinephrine levels in patients at rest were elevated with both hydrochlorothiazide and combination therapy when compared to that in patients with enalapril and control (p less than 0.05). Treatment with enalapril alone produced no changes in plasma catecholamine levels compared to control. There were no differences between control and all treatment regimens in peak exercise levels of catecholamines. Thus, enalapril, hydrochlorothiazide, and combination therapy, although effective in lowering resting blood pressure, may not be effective in blunting the blood-pressure response to exercise. The drugs do not appear to have any significant effects on catecholamine levels in patients at peak exercise.


Anti-hepatitis, antioxidant activities and bioactive compounds of Dracocephalum heterophyllum extracts.
Dracocephalum heterophyllum was a traditional Tibetan medicine possesses various pharmacological effects involved in anti-inflammatory, antibacterial activities. However, its anti-hepatitis, antioxidant activity and bioactive compounds have not been reported, the objective of this research work was to investigate the pharmacological activity and bioactive compounds of D. heterophyllum extracts. In the present study, the anti-hepatics and antioxidant activities of four D. heterophyllum extracts (i.e. petroleum ether extracts, ethyl acetate extracts, n-BuOH extracts, and water extracts) were conducted. The main chemical constituent of petroleum ether and ethyl acetate extracts were also isolated using chromatographic techniques and identified by NMR spectroscopic methods. The anti-hepatitis assay showed that the petroleum ether and ethyl acetate extracts of D. heterophyllum significantly prolonged the mean survival times and reduced the mortality of mouse hepatitis model induced by concanavalin A (ConA). The levels of alanine transaminase, aspartate transaminase in blood serum could be decreased obviously by ethyl acetate extracts compared with ConA group (P < 0.01). The histological analysis demonstrated that the ethyl acetate extracts could inhibit apoptosis and necrosis caused by ConA. In addition, the antioxidant activities of the four extracts of D. heterophyllum were measured by DPPH assay, ABTS assay, anti-lipidperoxidation assay, ferric reducing antioxidant power assay, ferrous metal ions chelating assay and determination of total phenolic contents. The results showed that the ethyl acetate extract had the highest antioxidant activities, followed by petroleum ether extract. Finally, nine mainly compounds were isolated from the Petroleum ether and ethyl acetate extracts, including four triterpenes: oleanolic acid (1), ursolic acid (2), pomolic acid (3), 2α- hydroxyl ursolic acid (4), three flavonoids: apigenin-7-O-rutinoside (5), luteolin (8), diosmetin (9) and two phenolic acids: rosmarinic acid (6), methyl rosmarinate (7). The Ethyl acetate extract of D. heterophyllum had the highest anti-hepatitis and antioxidants activities, followed by petroleum ether extract. The bioactive substances may be triterpenes, flavonoids and phenolic acids, the ethyl acetate extracts of D. heterophyllum may be possible candidates in developing anti-hepatitis medicine.


Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey.
To study patterns of co-occurrence of lifetime DSM-III-R alcohol disorders in a household sample. Data came from the National Comorbidity Survey (NCS), a nationally representative household survey. Diagnoses were based on a modified version of the Composite International Diagnostic Interview. Respondents with lifetime NCS/DSM-III-R alcohol abuse or dependence had a high probability of carrying at least 1 other lifetime NCS/DSM-III-R diagnosis. Retrospective reports have suggested that most lifetime co-occurring alcohol disorders begin at a later age than at least 1 other NCS/DSM-III-R disorder. Earlier disorders are generally stronger predictors of alcohol dependence than alcohol abuse and stronger among women than men. Lifetime co-occurrence is positively, but weakly, associated with the persistence of alcohol abuse among men and of alcohol dependence among both men and women. Caution is needed in interpreting the results due to the fact that diagnoses were made by nonclinicians and results are based on retrospective reports of the age at onset. Within the context of these limitations, though, these results show that alcohol abuse and dependence are often associated with other lifetime DSM-III-R disorders and suggest that, at least in recent cohorts, the alcohol use disorders are usually temporally secondary. Prospective data and data based on clinically confirmed diagnoses are needed to verify these findings.


Drugs against superbugs: private lessons from bacteriophages.
Bacterial genomics has provided a plethora of potential targets for antibacterial drug discovery, however, success in the hunt for new antibiotics will hinge on selecting targets with the highest potential. A recent paper by Liu and coworkers describes a new approach to target selection that uncovers strategies used by bacteriophage to disable bacteria. The method uses key phage proteins to identify and validate vulnerable targets and exploits them further in the identification of new antibacterial leads.


Ferredoxin 1b (Fdx1b) Is the Essential Mitochondrial Redox Partner for Cortisol Biosynthesis in Zebrafish.
Mitochondrial cytochrome P450 (CYP) enzymes rely on electron transfer from the redox partner ferredoxin 1 (FDX1) for catalytic activity. Key steps in steroidogenesis require mitochondrial CYP enzymes and FDX1. Over 30 ferredoxin mutations have been explored in vitro; however, no spontaneously occurring mutations have been identified in humans leaving the impact of FDX1 on steroidogenesis in the whole organism largely unknown. Zebrafish are an important model to study human steroidogenesis, because they have similar steroid products and endocrine tissues. This study aimed to characterize the influence of ferredoxin on steroidogenic capacity in vivo by using zebrafish. Zebrafish have duplicate ferredoxin paralogs: fdx1 and fdx1b. Although fdx1 was observed throughout development and in most tissues, fdx1b was expressed after development of the zebrafish interrenal gland (counterpart to the mammalian adrenal gland). Additionally, fdx1b was restricted to adult steroidogenic tissues, such as the interrenal, gonads, and brain, suggesting that fdx1b was interacting with steroidogenic CYP enzymes. By using transcription activator-like effector nucleases, we generated fdx1b mutant zebrafish lines. Larvae with genetic disruption of fdx1b were morphologically inconspicuous. However, steroid hormone analysis by liquid chromatography tandem mass spectrometry revealed fdx1b mutants failed to synthesize glucocorticoids. Additionally, these mutants had an up-regulation of the hypothalamus-pituitary-interrenal axis and showed altered dark-light adaptation, suggesting impaired cortisol signaling. Antisense morpholino knockdown confirmed Fdx1b is required for de novo cortisol biosynthesis. In summary, by using zebrafish, we generated a ferredoxin knockout model system, which demonstrates for the first time the impact of mitochondrial redox regulation on glucocorticoid biosynthesis in vivo.


Forest health and global change.
Humans rely on healthy forests to supply energy, building materials, and food and to provide services such as storing carbon, hosting biodiversity, and regulating climate. Defining forest health integrates utilitarian and ecosystem measures of forest condition and function, implemented across a range of spatial scales. Although native forests are adapted to some level of disturbance, all forests now face novel stresses in the form of climate change, air pollution, and invasive pests. Detecting how intensification of these stresses will affect the trajectory of forests is a major scientific challenge that requires developing systems to assess the health of global forests. It is particularly critical to identify thresholds for rapid forest decline, because it can take many decades for forests to restore the services that they provide.


Spinal Stimulation for the Treatment of Intractable Spine and Limb Pain: A Systematic Review of RCTs and Meta-Analysis.
To synthesize the evidence regarding the effect of spinal stimulation (SS) vs medical therapy (MT) and the effect of newer SS technologies vs conventional SS on pain reduction in patients with intractable spine or limb pain. A comprehensive literature search was conducted by a reference librarian. The literature search encompassed January 1, 1995 - December 31, 2017. Reviewers worked independently to select and appraise trials. Random-effect meta-analysis and frequentist indirect comparison methods were used to compare the three interventions. Results were expressed as odds ratio (OR) or weighted mean difference (WMD) with 95% CIs. We identified 12 trials enrolling 980 patients. Compared with MT, SS significantly increased the odds of reducing pain by 50% or more in three trials (OR, 13.01; 95% CI, 4.96-34.17) and significantly reduced pain as measured by visual analogue scale scores in three trials (WMD, 1.43 scale points; 95% CI, 0.16-2.71). Using the common comparator of MT, newer stimulation technology (eg, high-frequency 10 kilohertz spinal stimulation, Burst, dorsal root ganglion) was associated with increased odds of pain relief compared with conventional SS (OR, 2.07; 95% CI, 1.35-3.19). In patients with intractable spine/limb pain, SS was associated with better pain reduction than MT. New stimulation technology was likely associated with better pain reduction than conventional stimulation.


Ester cleavage properties of synthetic hydroxybenzotriazoles in cationic monovalent and gemini surfactant micelles.
Four new hydroxybenzotriazole derivatives have been synthesized. Two of them, N-tetradecyl-1-hydroxy-1H-benzo[d][1,2,3]triazole-6-carboxamide (2) and N-tetradecyl-1-hydroxy-1H-benzo[d][1,2,3]triazole-7-carboxamide (3), possess long alkyl chains, while the other two, 1-hydroxy-1H-benzo[d][1,2,3]triazole-6-carboxylic acid (4) and 1-hydroxy-1H-benzo[d][1,2,3]triazole-7-carboxylic acid (5), have carboxylate side chains. These compounds along with their parent unsubstituted 1-hydroxybenzotriazole (HOBt), 1, have been examined for the cleavage of p-nitrophenyl hexanoate (PNPH) and p-nitrophenyl diphenyl phosphate (PNPDPP) in comicelles with monovalent cetyltrimethylammonium bromide (CTABr) and the corresponding bis-cationic gemini surfactants 16-m-16, 2Br(-) of identical chain length at 25 degrees C and pH 8.2. The apparent pK(a) values of the HOBt derivatives in the comicelles of CTABr or 16-4-16 gemini surfactant have been determined from the rate versus pH profiles and were found to be comparable. Catalytic system 4/16-4-16 demonstrated over 2200- and 1650-fold rate enhancements in the hydrolysis of PNPDPP and PNPH, respectively, for identical reactions carried out at pH 8.2 and 25 degrees C in buffered aqueous media. The second-order rate constants for such bimolecular reactions were determined employing pseudophase micellar models. Experiments in which excess substrate was taken over HOBt derivatives demonstrated that the catalysts "turned over"; hydrolysis of the putative acylated or phosphorylated HOBt intermediates was rapid in either type of host micelles.


Nighttime Ecology: The "Nocturnal Problem" Revisited.
The existence of a synthetic program of research on what was then termed the "nocturnal problem" and that we might now call "nighttime ecology" was declared more than 70 years ago. In reality, this failed to materialize, arguably as a consequence of practical challenges in studying organisms at night and instead concentrating on the existence of circadian rhythms, the mechanisms that give rise to them, and their consequences. This legacy is evident to this day, with consideration of the ecology of the nighttime markedly underrepresented in ecological research and literature. However, several factors suggest that it would be timely to revive the vision of a comprehensive research program in nighttime ecology. These include (i) that the study of the ecology of the night is being revolutionized by new and improved technologies; (ii) suggestions that, far from being a minor component of biodiversity, a high proportion of animal species are active at night; (iii) that fundamental questions about differences and connections between the ecology of the daytime and the nighttime remain largely unanswered; and (iv) that the nighttime environment is coming under severe anthropogenic pressure. In this article, I seek to reestablish nighttime ecology as a synthetic program of research, highlighting key focal topics and questions and providing an overview of the current state of understanding and developments.


Reducing errors through a web-based self-management support system.
Web-based self-management support systems SMSS, can successfully assist a wide range of patients with information and self-management support. O or as a stand-alone service, are e-messages. This study describes how one component of a multi component SMSS, an e-message service, in which patients with breast cancer could direct questions to nurses, physicians or social workers at the hospital where they were being treated, had an influence on safety and continuity of care. Ninety-one dialogues consisting of 284 messages were analysed. The communications between patients and the healthcare team revealed that the e-messages service served as a means for quality assurance of information, for double-checking and for coordination of care. We give examples of how an e-mail service may improve patients' knowledge in a process of taking control over their own care - increasingly important in a time of growing complexity and specialization in healthcare. It remains to be tested whether an e-message service can improve continuity of care and prevent or mitigate medical mishaps.


NTP Toxicology and Carcinogenesis Studies of C.I. Basic Red 9 Monohydrochloride (Pararosaniline) (CAS No. 569-61-9) In F344/N Rats and B6C3F1 Mice (Feed Studies).
C.I. Basic Red 9 monohydrochloride is a triphenylmethane dye used for coloring textiles, leather, and paper and as a biological stain. Toxicology and carcinogenesis studies were conducted by administering the test chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice for 103 weeks at concentrations of 0, 1,000, or 2,000 ppm for male rats and 0, 500, or 1,000 ppm for female rats and mice of each sex. The average daily doses of C.I. Basic Red 9 monohydrochloride were estimated to be 49 and 103 mg/kg for male rats, 28 and 59 for female rats, 196 and 379 mg/kg for male mice, and 149 and 407 mg/kg for female mice. Two lots of the test chemical were used in the 2-year studies with purities of 93% (water content approximately 9%) and 99%. In rats, the thyroid gland and pituitary gland were identified as target sites in the 13-week studies. Therefore, 10 additional rats of each sex were added to the control and high dose groups in the 2-year studies to examine the effects on these organs after 1 year of exposure. In the 1-year studies in rats, final mean body weights were slightly decreased in both sexes. The thyroid gland weight to body ratio of dosed males was 1.7 times that of the controls, and the concentration of serum thyroxin in male and female rats was significantly lower than that of the controls at week 52. Compound-related histopathologic effects included thyroid gland cysts in both sexes (1/10; 1/10) and thyroid gland follicular cell hyperplasia (1/10), adenomas (1/10), and carcinomas (1/10) and fatty metamorphosis of the liver (4/10, two of these with focal necrosis) in males; no effect was seen in the controls. The doses selected for the 2-year studies were based on the results of the 13-week studies. The absence of toxicologic signs, histopathologic changes, significant body weight depressions, or mortality after 13 weeks of exposure to C.I. Basic Red 9 monohydrochloride suggested that these concentrations would not shorten survival. However, throughout the 2-year studies, mean body weights of high dose rats and dosed mice were lower than those of the controls, and significantly reduced survival relative to controls was observed for high dose rats of each sex (P<0.001), low dose male mice (P<0.03), and low dose and high dose female mice (P<0.001). In the 2-year studies, several types of neoplastic lesions occurred with significantly increased incidences in dosed animals (see table page 12 of the Technical Report). High dose male rats had increased incidences of squamous cell carcinomas, trichoepitheliomas, and sebaceous adenomas of the skin. Greater incidences of follicular cell carcinomas and of follicular cell adenomas were found in the thyroid glands of high dose male rats than in controls, whereas in high dose female rats, the combined incidence of follicular cell adenomas or carcinomas was greater than that in controls. Dosed rats of each sex had increased incidences of subcutaneous fibromas, and high dose rats had increased incidences of Zymbal gland carcinomas. Hepatocellular carcinomas were the compound-related neoplasms common to both species; the incidences were increased in both high dose male rats and in dosed mice of each sex. Dosed female mice had an increased incidence of pheochromocytomas or malignant pheochromocytomas. In addition, marginally increased incidences of mammary gland tumors (23/50; 32/50; 32/50) in female rats, and malignant lymphomas (17/50; 24/50; 25/50) in female mice were observed. C.I. Basic Red 9 monohydrochloride was mutagenic in strains TA98 and TA100 of Salmonella typhimurium by the preincubational protocol with or without metabolic activation. It was not mutagenic in strains TA1535 and TA1537 in this system with or without metabolic activation. It was mutagenic in the L5178Y/TK+/- mouse lymphoma assay with or without metabolic activation. C.I. Basic Red 9 monohydrochloride did not induce chromosomal aberrations in Chinese hamster ovary cells; it did induce sister-chromatid exchanges in the presence of Aroclor 1254-induced male Sprague-Dawley rat li-induced male Sprague-Dawley rat liver S9. C.I. Basic Red 9 monohydrochloride also induced unscheduled DNA synthesis in F344 male rat hepatocytes in vitro. An audit of the experimental data was conducted for these 2-year studies of C.I. Basic Red 9 monohydrochloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenicity of C.I. Basic Red 9 monohydrochloride for male and female F344/N rats and for male and female B6C3F1 mice. In male rats, C.I. Basic Red 9 monohydrochloride caused squamous cell carcinomas, trichoepitheliomas and sebaceous adenomas of the skin, subcutaneous fibromas, thyroid gland follicular cell adenomas and follicular cell carcinomas, Zymbal gland carcinomas, and hepatocellular carcinomas. In female rats, C.I. Basic Red 9 monohydrochloride caused subcutaneous fibromas, thyroid gland follicular cell adenomas or carcinomas (combined), and Zymbal gland carcinomas. In male mice, C.I. Basic Red 9 monohydrochloride caused hepatocellular carcinomas. In female mice, C.I. Basic Red 9 monohydrochloride caused hepatocellular carcinomas and adrenal gland pheochromocytomas or malignant pheochromocytomas (combined). Exposure to C.I. Basic Red 9 monohydrochloride also may have been related to increased incidences of mammary gland tumors in female rats and hematopoietic system tumors in female mice. Synonyms: pararosaniline; benzeneamine 4-((4-aminophenyl)(4-imino-2,5-cyclohexadian-1-ylidene)methyl)-monohydrochloride paramagenta


Achalasia presenting as acute stridor.
We report a case of achalasia presenting as acute stridor and respiratory distress in an 87-year-old woman. A mega-oesophagus was decompressed by aspiration through a naso-oesophageal tube, stiffened with paediatric endoscopic biopsy forceps before placement. Subsequent barium swallow showed mega-oesophagus secondary to achalasia causing tracheal compression at the level of the thoracic inlet. There have been 28 previous case reports of mega-oesophagus due to achalasia causing tracheal obstruction and the literature is reviewed. Recognition and urgent treatment of this very rare complication of achalasia by naso-oesophageal decompression may avoid fatality.


The gut microbiota appears to compensate for seasonal diet variation in the wild black howler monkey (Alouatta pigra).
For most mammals, including nonhuman primates, diet composition varies temporally in response to differences in food availability. Because diet influences gut microbiota composition, it is likely that the gut microbiota of wild mammals varies in response to seasonal changes in feeding patterns. Such variation may affect host digestive efficiency and, ultimately, host nutrition. In this study, we investigate the temporal variation in diet and gut microbiota composition and function in two groups (N = 13 individuals) of wild Mexican black howler monkeys (Alouatta pigra) over a 10-month period in Palenque National Park, Mexico. Temporal changes in the relative abundances of individual bacterial taxa were strongly correlated with changes in host diet. For example, the relative abundance of Ruminococcaceae was highest during periods when energy intake was lowest, and the relative abundance of Butyricicoccus was highest when young leaves and unripe fruit accounted for 68 % of the diet. Additionally, the howlers exhibited increased microbial production of energy during periods of reduced energy intake from food sources. Because we observed few changes in howler activity and ranging patterns during the course of our study, we propose that shifts in the composition and activity of the gut microbiota provided additional energy and nutrients to compensate for changes in diet. Energy and nutrient production by the gut microbiota appears to provide an effective buffer against seasonal fluctuations in energy and nutrient intake for these primates and is likely to have a similar function in other mammal species.


Australian Gay Men Describe the Details of Their HIV Infection Through a Cross-Sectional Web-Based Survey.
With emerging opportunities for preventing human immunodeficiency virus (HIV) transmission, it remains important to identify those at greatest risk of infection and to describe and understand the contexts in which transmissions occur. Some gay and bisexual men with recently diagnosed HIV infection are initially unable to identify high-risk behaviors that would explain their HIV infection. We explored whether Web-based data collection could assist them in identifying the circumstances of their infection. To assess the capacity of a Web-based survey to collect reliable self-report data on the event to which gay and bisexual men ascribe their HIV infection. The HIV Seroconversion Study included a Web-based survey of gay and bisexual men with recently diagnosed HIV infection in Australia. Participants were asked if they could identify and describe the event they believe led to their infection. Men were also asked about their sexual and other risk practices during the 6 months before their diagnosis. Most (403/506, 79.6%) gay and bisexual men with newly diagnosed HIV infection were able to identify and describe the circumstances that likely led to their infection. Among those who were initially unable to identify possible exposure events, many could nonetheless provide sensible information that ostensibly explained their seroconversion. Free-text responses allowed men to provide more detailed and contextual information, whereas questions about the totality of their sexual behavior before diagnosis provided opportunities for men to describe their sexual risk behavior in general. Overall, 84.0% indicated having engaged in condomless anal intercourse before their HIV diagnosis, including 71.8% in the receptive position. This study demonstrates the effectiveness of using Internet-based technologies to capture sensitive information about the circumstances in which HIV infection occurs among gay and bisexual men. By providing a range of opportunities for relaying experience, this research reveals some of the complexity in how individuals come to understand and explain their HIV infection. These findings may assist in obtaining detailed sexual history in the clinical setting.


Hygiene of venepuncture tourniquets in Denmark.
Tourniquets are widely used to make the vein more visible prior to blood collection. Venepuncture tourniquets are however a non-sterile and potentially reusable equipment. Several studies have shown that they are colonised by a variety of pathogenic bacteria and consecutively use of the same tourniquet on multiple patients will increase the risk of a nosocomial infection. This matter is however only scarcely studied. The objective of this study was to investigate the nationwide use of disposable and non-disposable venepuncture tourniquets and the standardised procedures for cleaning the tourniquets. A questionnaire concerning use and cleaning of tourniquets was therefore sent to all major Danish clinical biochemistry laboratories (n = 12). All but one laboratory had a local procedure for usage and handling of tourniquets, including structured procedures for cleaning. Despite this, only 75% of laboratories had a guideline for cleaning the tourniquets and only 50% had a specified cleaning program. At the hospitals using non-disposable tourniquets the handling differed considerably and at two hospitals the tourniquets were only cleaned once a week, while one laboratory did not clean the tourniquet before it was visibly stained. Of note, five of the eight hospitals using disposable tourniquets only disposed the tourniquets on a daily basis. In conclusion, there is a lack of guidelines for handling tourniquets in 25-33% of the hospitals and a number of hospitals used both types (disposable and non-disposable), which could confuse the handling of the tourniquets. A national guideline for usage and cleaning of venepuncture tourniquets is therefore strongly recommended.


Reduced fertilization after ICSI and abnormal phospholipase C zeta presence in spermatozoa from the wobbler mouse.
Failed fertilization after intracytoplasmic sperm injection (ICSI) can be due to a reduced oocyte-activation capacity caused by reduced concentrations and abnormal localization of the oocyte-activation factor phospholipase C (PLC) zeta. Patients with this condition can be helped to conceive by artificial activation of oocytes after ICSI with calcium ionophore (assisted oocyte activation; AOA). However some concern still exists about this approach. Mouse models could help to identify potential oocyte-activation strategies and evaluate their safety. In this study, the fertilizing capacity of wobbler sperm cells was tested and the efficiency of AOA with two exposures to ionomycin to restore fertilization and embryo development was studied. The quality of the obtained blastocysts was assessed and embryo transfer was performed to evaluate post-implantation development. The presence of PLCzeta in the spermatozoa and testis of the wobbler mouse was evaluated by PLCzeta immunostaining and quantitative reverse-transcription polymerase chain reaction. Sperm cells from wobbler mice had reduced fertilizing capacity and abnormalities in PLCzeta localization, but not in its expression. Artificially activating the oocytes restored fertilization and embryo development. Therefore, the wobbler mouse can be a model for failed fertilization after ICSI to study PLCzeta dynamics and aid in optimization of the AOA method.


Blunting of the renal response to volume expansion by a bradykinin receptor antagonist: influence of denervation.
The interaction of renal sympathetic nervous influences with the intrarenal kallikrein-kinin system was examined during graded expansion of the extracellular fluid volume in rats. One group of rats was pretreated with a specific and highly efficacious competitive antagonist of bradykinin receptor (BKRA), whereas the other group received only a vehicle infusion. The left kidney was denervated in each animal and the right kidney remained intact. After control observations, the extracellular fluid volume was expanded by a continuous i.v. infusion of 0.9% NaCl at a rate of 0.25% of body weight per minute for 40 min (VE). During VE urine flow and sodium excretion increased significantly from both kidneys in each of the two treatment groups. The diuretic response was greatest in the denervated kidneys of vehicle-pretreated rats, where urine flow increased by 70 +/- 13 microliters.min(-1).g kwt(-1). This exaggerated diuresis was blunted by pretreatment with the BKRA. In the denervated and BKRA-treated kidneys, the VE-induced mean urine flow increase was limited to 31 +/- 5 microliters.min(-1).g kwt(-1) (P less than .05 compared with vehicle-pretreated, denervated kidneys). The change in net sodium excretion produced by VE was also reduced by BKRA pretreatment in the denervated kidneys from 13.2 +/- 2.6 to 5.5 +/- 1.3 microEq.min-1.g kwt(-1) (P less than .05, vehicle vs. BKRA). In the intact kidneys the diuretic and natriuretic responses to VE were similar in the vehicle- and BKRA-pretreated rats. Glomerular filtration rate and filtration fraction were increased significantly and to the same extent by VE under all experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)


Physical binding pocket induction for affinity prediction.
Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have limited utility when structural variation moves beyond congeneric series. We present a novel approach based on the multiple-instance learning method of Compass, where a physical model of a binding site is induced from ligands and their corresponding activity data. The model consists of molecular fragments that can account for multiple positions of literal protein residues. We demonstrate the method on 5HT1a ligands by training on a series with limited scaffold variation and testing on numerous ligands with variant scaffolds. Predictive error was between 0.5 and 1.0 log units (0.7-1.4 kcal/mol), with statistically significant rank correlations. Accurate activity predictions of novel ligands were demonstrated using a validation approach where a small number of ligands of limited structural variation known at a fixed time point were used to make predictions on a blind test set of widely varying molecules, some discovered at a much later time point.


Psychiatric nurses' descriptions of women with postpartum psychosis and nurses' responses--an exploratory study in Sweden.
Postpartum psychosis is the most serious type of psychiatric illness related to childbirth. This interview study with nine psychiatric nurses in Sweden explored psychiatric nurses' descriptions of women with psychosis occurring in the postpartum period and nurses' responses when providing care to these women. Content analysis was used to analyze the data. The nurses described delusions, disconnection, aggression, changed personality, self-absorption, insomnia, chaos, quietness, suicidal ideation, and 'strange eyes.' The description of strange eyes noted by the nurses has not been found in the literature, warranting further investigation. When providing care, the nurses responded with sadness, sympathy, empathy and compassion, discomfort, anger, anxiety, and happiness. These findings underscore the importance of nurses recognizing their negatively charged emotions which could interfere with providing compassionate and effective nursing care to this population.


Impeding Earl Warren: California's health insurance plan that wasn't and what might have been.
It is widely believed that the turning point for U.S. health insurance came in 1949 when Congress failed to adopt President Harry Truman's proposal for a national system. The possibility that a system of state-level health plans might have emerged before Truman's plan has received little attention. Yet several attempts to enact such a plan were made in California by Governor Earl Warren in the mid-1940s. Had Warren succeeded, the California example might have been emulated by other states and the United States might have evolved a system similar to Canada's provincial programs.


Epigenetic impacts on neurodevelopment: pathophysiological mechanisms and genetic modes of action.
Disruptions of genes that are involved in epigenetic functions are known to be causative for several mental retardation/intellectual disability (MR/ID) syndromes. Recent work has highlighted genes with epigenetic functions as being implicated in autism spectrum disorders (ASDs) and schizophrenia (SCZ). The gene-environment interaction is an important factor of pathogenicity for these complex disorders. Epigenetic modifications offer a mechanism by which we can explain how the environment interacts with, and is able to dynamically regulate, the genome. This review aims to provide an overview of the role of epigenetic deregulation in the etiopathology for neurodevelopment disease.


Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes.
Torsade de pointes is a rare but potentially fatal ventricular arrhythmia that is often triggered by drugs that prolong the rate-corrected QT (QTc) interval. This arrhythmia has been attributed to levacetylmethadol and methadone, synthetic opioids used to treat heroin addiction. Levacetylmethadol, a derivative of methadone, is being withdrawn from the United States market because its use waned after a black box warning was issued to require electrocardiographic monitoring. Therefore, methadone and buprenorphine are the only opioids available for the treatment of heroin addiction. To our knowledge, the cardiac safety of buprenorphine in patients with methadone-related QTc prolongation has not been described. We report a patient who developed torsade de pointes while receiving high-dose methadone and was successfully inducted onto buprenorphine under close medical supervision. No clinically important QTc prolongation was observed in the acute setting or during follow-up. This observation suggests that buprenorphine may be a safe alternative to oral methadone in patients with opioid addiction who develop torsade de pointes.


BusyBee Web: metagenomic data analysis by bootstrapped supervised binning and annotation.
Metagenomics-based studies of mixed microbial communities are impacting biotechnology, life sciences and medicine. Computational binning of metagenomic data is a powerful approach for the culture-independent recovery of population-resolved genomic sequences, i.e. from individual or closely related, constituent microorganisms. Existing binning solutions often require a priori characterized reference genomes and/or dedicated compute resources. Extending currently available reference-independent binning tools, we developed the BusyBee Web server for the automated deconvolution of metagenomic data into population-level genomic bins using assembled contigs (Illumina) or long reads (Pacific Biosciences, Oxford Nanopore Technologies). A reversible compression step as well as bootstrapped supervised binning enable quick turnaround times. The binning results are represented in interactive 2D scatterplots. Moreover, bin quality estimates, taxonomic annotations and annotations of antibiotic resistance genes are computed and visualized. Ground truth-based benchmarks of BusyBee Web demonstrate comparably high performance to state-of-the-art binning solutions for assembled contigs and markedly improved performance for long reads (median F1 scores: 70.02-95.21%). Furthermore, the applicability to real-world metagenomic datasets is shown. In conclusion, our reference-independent approach automatically bins assembled contigs or long reads, exhibits high sensitivity and precision, enables intuitive inspection of the results, and only requires FASTA-formatted input. The web-based application is freely accessible at: https://ccb-microbe.cs.uni-saarland.de/busybee.


Mobility in Blue-Green Spaces Does Not Predict COVID-19 Transmission: A Global Analysis.
Mobility restrictions during the COVID-19 pandemic ostensibly prevented the public from transmitting the disease in public places, but they also hampered outdoor recreation, despite the importance of blue-green spaces (e.g., parks and natural areas) for physical and mental health. We assess whether restrictions on human movement, particularly in blue-green spaces, affected the transmission of COVID-19. Our assessment uses a spatially resolved dataset of COVID-19 case numbers for 848 administrative units across 153 countries during the first year of the pandemic (February 2020 to February 2021). We measure mobility in blue-green spaces with planetary-scale aggregate and anonymized mobility flows derived from mobile phone tracking data. We then use machine learning forecast models and linear mixed-effects models to explore predictors of COVID-19 growth rates. After controlling for a number of environmental factors, we find no evidence that increased visits to blue-green space increase COVID-19 transmission. By contrast, increases in the total mobility and relaxation of other non-pharmaceutical interventions such as containment and closure policies predict greater transmission. Ultraviolet radiation stands out as the strongest environmental mitigant of COVID-19 spread, while temperature, humidity, wind speed, and ambient air pollution have little to no effect. Taken together, our analyses produce little evidence to support public health policies that restrict citizens from outdoor mobility in blue-green spaces, which corroborates experimental studies showing low risk of outdoor COVID-19 transmission. However, we acknowledge and discuss some of the challenges of big data approaches to ecological regression analyses such as this, and outline promising directions and opportunities for future research.


Impact of chronic plantar heel pain on health-related quality of life.
Chronic plantar heel pain (CPHP) is common and is thought to have a detrimental impact on health-related quality of life. However, no study has used normative data or a control data set for comparison of scores. Therefore, we describe the impact of CPHP on foot-specific and general health-related quality of life by comparing CPHP subjects with controls. Foot Health Status Questionnaire scores were compared in 80 subjects with CPHP and 80 sex- and age-matched controls without CPHP. The CPHP group demonstrated significantly poorer foot-specific quality of life, as evidenced by lower scores on the foot pain, foot function, footwear, and general foot health domains of the Foot Health Status Questionnaire. The group also demonstrated significantly poorer general health-related quality of life, with lower scores on the physical activity, social capacity, and vigor domains. In multivariate analysis, CPHP remained significantly and independently associated with Foot Health Status Questionnaire scores after adjustment for differences in body mass index. Age, sex, body mass index, and whether symptoms were unilateral or bilateral had no association with the degree of impairment in people with CPHP. Chronic plantar heel pain has a significant negative impact on foot-specific and general health-related quality of life. The degree of negative impact does not seem to be associated with age, sex, or body mass index.


Effects of Hofmeister anions on the phase transition temperature of elastin-like polypeptides.
The modulation of the lower critical solution temperature (LCST) of two elastin-like polypeptides (ELPs) was investigated in the presence of 11 sodium salts that span the Hofmeister series for anions. It was found that the hydrophobic collapse/aggregation of these ELPs generally followed the series. Specifically, kosmotropic anions decreased the LCST by polarizing interfacial water molecules involved in hydrating amide groups on the ELPs. On the other hand, chaotropic anions lowered the LCST through a surface tension effect. Additionally, chaotropic anions showed salting-in properties at low salt concentrations that were related to the saturation binding of anions with the biopolymers. These overall mechanistic effects were similar to those previously found for the hydrophobic collapse and aggregation of poly(N-isopropylacrylamide), PNIPAM. There is, however, a crucial difference between PNIPAM and ELPs. Namely, PNIPAM undergoes a two-step collapse process as a function of temperature in the presence of sufficient concentrations of kosmotropic salts. By contrast, ELPs undergo collapse in a single step in all cases studied herein. This suggests that the removal of water molecules from around the amide moieties triggers the removal of hydrophobic hydration waters in a highly coupled process. There are also some key differences between the LCST behavior of the two ELPs. Specifically, the more hydrophilic ELP V5A2G(3)-120 construct displays collapse/aggregation behavior that is consistent with a higher concentration of anions partitioning to polymer/aqueous interface as compared to the more hydrophobic ELP V(5)-120. It was also found that larger anions could bind with ELP V5A2G(3)-120 more readily in comparison with ELP V(5)-120. These latter results were interpreted in terms of relative binding site accessibility of the anion for the ELP.


Does Caffeine Increase Fat Metabolism? A Systematic Review and Meta-Analysis.
Whether caffeine (CAF) increases fat metabolism remains debatable. Using systematic review coupled with meta-analysis, our aim was to determine effects of CAF on fat metabolism and the relevant factors moderating this effect. Electronic databases PubMed, SPORTDiscus, and Web of Science were searched using the following string: CAF AND (fat OR lipid) AND (metabolism OR oxidation). A meta-analytic approach aggregated data from 94 studies examining CAF's effect on fat metabolism assessed by different biomarkers. The overall effect size (ES) was 0.39 (95% confidence interval [CI] [0.30, 0.47], p < .001), indicating a small effect of CAF to increase fat metabolism; however, ES was significantly higher (p < .001) based on blood biomarkers (e.g., free fatty acids, glycerol) (ES = 0.55, 95% CI [0.43, 0.67]) versus expired gas analysis (respiratory exchange ratio, calculated fat oxidation) (ES = 0.26, 95% CI [0.16, 0.37]), although both were greater than zero. Fat metabolism increased to a greater extent (p = .02) during rest (ES = 0.51, 95% CI [0.41, 0.62]) versus exercise (ES = 0.35, 95% CI [0.26, 0.44]) across all studies, although ES was not different for studies reporting both conditions (ES = 0.49 and 0.44, respectively). There were no subgroup differences based on participants' fitness level, sex, or CAF dosage. CAF ingestion increases fat metabolism but is more consistent with blood biomarkers versus whole-body gas exchange measures. CAF has a small effect during rest across all studies, although similar to exercise when compared within the same study. CAF dosage did not moderate this effect.


Pedophilic behavior from brain disease.
Child molestation or other pedophilic behavior may result as a consequence of a brain disorder. To characterize the mechanisms of pedophilic behavior associated with neurological diseases. We report eight patients with pedophilic behavior as a manifestation of their brain disorder and review the literature. The sexual, neuropsychiatric, and neurological aspects of a series of patients. All eight developed sexual behavior toward prepubescent children in mid- to late-life coincident with the development of a neurological disorder. Five had limited insight, anxiety, or concern for their behavior and tended to have frontal lobe executive deficits. Most of this group had frontally predominant disorders. Two others retained insight and concern in the context of marked hypersexuality. This second group had treated Parkinson's disease and resembled reports of pedophilic behavior from subcortical lesions. The further presence of right temporal lobe-amygdala involvement may have predisposed to specific sexual preoccupation in some patients. Brain disorders may release a predisposition to sexual attraction for children through disinhibition with frontal disease, sexual preoccupation with right temporal disease, or hypersexuality with subcortical disease in non-motor basal ganglia, hypothalamus, or septal nuclei. Differentiating these mechanisms of pedophilic behavior from brain disease could facilitate targeted interventions.


Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.
Immunoglobulin (Ig) antigen receptors are composed of a noncovalently-associated complex of Ig and two other proteins, Ig alpha and Ig beta. The cytoplasmic domain of both of these Ig associated proteins contains a consensus sequence that is shared with the signaling proteins of the T cell and Fc receptor. To test the idea that Ig alpha-Ig beta heterodimers are the signaling components of the Ig receptor, we have studied Ig mutations that interfere with signal transduction. We find that specific mutations in the transmembrane domain of Ig that inactivate Ca2+ and phosphorylation responses also uncouple IgM from Ig alpha-Ig beta. These results define amino acid residues that are essential for the assembly of the Ig receptor. Further, receptor activity can be fully reconstituted in Ca2+ flux and phosphorylation assays by fusing the cytoplasmic domain of Ig alpha with the mutant Igs. In contrast, fusion of the cytoplasmic domain of Ig beta to the inactive Ig reconstitutes only Ca2+ responses. Thus, Ig alpha and Ig beta are both necessary and sufficient to mediate signal transduction by the Ig receptor in B cells. In addition, our results suggest that Ig alpha and Ig beta can activate different signaling pathways.


Bacterial etiology of acute otitis media in the era prior to universal pneumococcal vaccination in Taiwanese children.
Acute otitis media (AOM) is one of the most frequent bacterial infections in children. Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) are the two major bacterial pathogens. Pneumococcal conjugate vaccine was introduced into Taiwan in 2005 and only some children were vaccinated. This retrospective study assessed the bacterial etiology of AOM and its antimicrobial susceptibility in the era prior to universal pneumococcal vaccination in Taiwan. From December 2009 to November 2011, children presenting with AOM and having a middle ear effusion sample collected by tympanocentesis were enrolled. The study period was divided into two parts. Demographic data of patients and antibiotic susceptibility of the pathogens were collected and analyzed. Serotypes of S. pneumoniae were identified. Among the 151 episodes, 46% of samples found bacterial pathogens. S. pneumoniae and NTHi were the leading causes of AOM, detected in 55.7% and 22.9% of bacterial AOM episodes, respectively. The prevalent serotypes of S. pneumoniae were 19 A and 19 F. Significantly more pneumococcal and serotype 19 A AOM were found in the later study period (18.4% vs. 33.3%, p = 0.0036; 10.5% vs. 24.0%, p = 0.028). Among the 39 S. pneumoniae isolates, 11 strains (28.2%) were penicillin-susceptible. Of the 16 NTHi, 10 (62.5%) were susceptible to amoxicillin/clavulanate and all were susceptible to cefotaxime. S. pneumoniae and NTHi were the leading causes of AOM in Taiwanese children in the study period. An increase in patient numbers and proportion of pneumococcal and serotype 19 A AOM occurred. Antimicrobial nonsusceptibility was common in the predominant pathogens.


Diagnosis of primary bone tumors with image-guided percutaneous biopsy: experience with 110 tumors.
To determine the diagnostic accuracy of image-guided percutaneous biopsy in 110 primary bone tumors of varying internal compositions. One hundred ten consecutive patients with primary bone tumors underwent biopsy with computed tomography (CT) or fluoroscopy. Ninety-one patients underwent surgical follow-up and 19 received medical treatment and underwent subsequent imaging studies. Final analysis of bone biopsy results included tumor type, malignancy, final tumor grade, biopsy complications, and effect on eventual treatment outcome. Seventy-seven tumors were malignant and 33 were benign. Most common tumors at biopsy were osteosarcoma (n = 20), lymphoma (n = 18), chondrosarcoma (n = 16), and giant cell tumor (n = 16). Correct final diagnosis was attained in 97 (88%) patients. Sixty-three lesions were solid nonsclerotic; 26, sclerotic; and 21, lytic with cystic centers containing internal areas of fluid, hemorrhage, or necrosis. In six of 21 lesions with a predominant cystic internal composition, problems occurred in determining a final diagnosis. In 13 patients, definite correct diagnosis was not obtained with initial percutaneous bone biopsy. Of these patients, benign bone tumors were better defined with surgical specimens in seven, a diagnosis of malignancy was changed to that of another malignancy in four, and the diagnosis was changed from benign to malignant in two. Nine patients underwent open surgical biopsy. Seven of the difficult cases were of cystic tumors with hemorrhagic fluid levels visible at CT or magnetic resonance imaging. The only complication was a small hematoma. Percutaneous biopsy of primary bone tumors is safe and accurate for diagnosis and grade of specific tumor. In cases with nondiagnostic biopsy, open-procedure biopsy is likely to be associated with similar diagnostic difficulties.


Expression and distribution of P450-aromatase in the ovine hypothalamus at different stages of fetal development.
An important step of sexual differentiation is the conversion of testosterone to estrogen by aromatase leading to masculinization and defeminization of the fetal brain areas crucial for normal sexual behavior and reproduction. Brain sexual differentiation occurs throughout a critical period starting from different prenatal stages depending on the species. Such period goes on from gestation day (GD) 30 to 100GD in the sheep. The fetal sheep brain is reported to aromatize androgens to estrogens at 64GD. The main goal of this work was to evaluate aromatase expression in sheep hypothalami during the whole period of sexual differentiation (35GD, 55GD, 80GD, 115GD) and whether differences may be observed depending on gestational stage and sex. Sections at the hypothalamic level underwent immunoperoxidase technique employing anti-aromatase and anti-androgen receptor antibodies. Samples from 35GD and 55GD were also processed with in situ hybridization using aromatase cDNA probe. Blot analyses were performed to quantify possible aromatase immunoexpression differences between sexes. For sexing, samples at 35GD and 55GD underwent DNA extraction and SRY amplification. Our results revealed aromatase and androgen receptor immunoreactivity along the whole period of sexual differentiation. Both molecules were detected in many brain regions and markedly in the periventricular area. The highest aromatase and androgen receptor amounts were observed at 35GD and 55GD, when aromatase was more abundant in females than in males. In conclusion, the sheep can be included among the species where aromatase is highly expressed in the hypothalamus during the whole period of sexual differentiation.


Triterpenoids as inhibitors of erythrocytic and liver stages of Plasmodium infections.
Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of two new cucurbitane-type triterpenoids, balsaminol F (1) and balsaminoside B (2), along with the known glycosylated cucurbitacins, cucurbita-5,24-diene-3β,23(R)-diol-7-O-β-D-glucopyranoside (3) and kuguaglycoside A (4). Compound 1 was acylated yielding two new triesters, triacetylbalsaminol F (5) and tribenzoylbalsaminol F (6). The structures were elucidated based on spectroscopic methods including 2D-NMR experiments (COSY, HMQC, HMBC and NOESY). Compounds 1-6, were evaluated for their antimalarial activity against the erythrocytic stages of the Plasmodium falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant clone Dd2. Assessment of compounds (1-3 and 5, 6) activity against the liver stage of Plasmodium berghei was also performed, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luc(con). Active compounds were shown to inhibit the parasite's intracellular development rather than its ability to invade hepatic cells. Toxicity of compounds (1-3 and 5, 6) was assessed on the same cell line and on mouse primary hepatocytes through the fluorescence measurement of cell confluency. Furthermore, toxicity of compounds 1-6 towards human cells was also investigated in the MCF-7 breast cancer cell line, showing that they were not toxic or exhibited weak toxicity. In blood stages of P. falciparum, compounds 1-5 displayed antimalarial activity, revealing triacetylbalsaminol F (5) the highest antiplasmodial effects (IC(50) values: 0.4μM, 3D7; 0.2μM, Dd2). The highest antiplasmodial activity against the liver stages of P.berghei was also displayed by compound 5, with high inhibitory activity and no toxicity.


Lizard threat display handicaps endurance.
Honest-signalling theory asserts that threat displays reliably advertise attributes that influence fighting success. Endurance, as measured by treadmill performance, predicts the outcome of agonistic interactions among lizards. If threat displays in lizards function to advertise endurance capacity then variation in threat displays should correlate with endurance. I tested this prediction for the duration of threat posturing in male side-blotched lizards (Uta stansburiana) and examined whether threat displays act as quality handicaps, reliable signals that expend the attribute that is advertised. Individual variation in the duration of threat posturing correlated with endurance, while an experimental reduction of endurance diminished the duration of threat posturing. As expected of a quality handicap, endurance fell below baseline after display production. A restriction of aerobic metabolism can account for this effect. In threat posturing, lateral compression of the thorax may interfere with respiration or with circulation, limiting aerobic metabolism and causing a compensatory increase in anaerobic metabolism, thereby generating lactate and diminishing locomotor capacity. Concentrations of lactate measured after display production were higher than baseline, consistent with the proposed mechanism. By restricting aerobic metabolism, the threat posture can act as a quality handicap, simultaneously advertising and expending the endurance capacity of displaying lizards.


Clinical trials of disease-modifying agents in pediatric MS: Opportunities, challenges, and recommendations from the IPMSSG.
The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety. The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population. In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease. It is imperative to reconsider study design and implementation based on what information is needed. Are studies needed for efficacy or should safety be the primary goal? Further, there have been major recruitment challenges in recently completed and ongoing pediatric MS trials. Phase 3 trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible. A primary goal is to ensure high-quality evidence-based treatment for children and adolescents with MS, which will improve our understanding of the safety of these agents and remove regulatory or insurance-based limitations in access to treatment.


Substrate tolerant direct block copolymer nanolithography.
Block copolymer (BC) self-assembly constitutes a powerful platform for nanolithography. However, there is a need for a general approach to BC lithography that critically considers all the steps from substrate preparation to the final pattern transfer. We present a procedure that significantly simplifies the main stream BC lithography process, showing a broad substrate tolerance and allowing for efficient pattern transfer over wafer scale. PDMS-rich poly(styrene-b-dimethylsiloxane) (PS-b-PDMS) copolymers are directly applied on substrates including polymers, silicon and graphene. A single oxygen plasma treatment enables formation of the oxidized PDMS hard mask, PS block removal and polymer or graphene substrate patterning.


Training volume and soft tissue injury in professional and non-professional rugby union players: a systematic review.
To investigate the relationship between training volume and soft tissue injury incidence, and characterise soft tissue injury in rugby union players. A systematic search of electronic databases was performed. The search strategy combined terms covering: training volume and injury, and rugby union, and players of all levels. Medline, SPORTDiscus, Web of Science, Embase, PubMed. Studies were included if they reported: male rugby union players, a clear definition of a rugby union injury, the amount of training volume undertaken by participants, and epidemiological data for soft-tissue injuries including the number or incidence. 15 studies were eligible for inclusion. Overall match and training injury incidence ranged from 3.3 to 218.0 injuries/1000 player match hours and 0.1-6.1 injuries/1000 player training hours, respectively. Muscle and tendon as well as joint (non-bone) and ligament injuries were the most frequently occurring injuries. The lower limb was the most prevalent injury location. Injury incidence was higher in professional rugby union players than non-professional players. Contact events were responsible for the greatest injury incidence. For non-contact mechanisms, running was responsible for the highest injury incidence. Inconsistent injury definitions hindered reliable comparison of injury data. The lack of reporting training volumes in hours per player per week limited the ability to investigate associations between training volume and injury incidence. A higher level of play may result in higher match injury incidence. Muscle and tendon injuries were the most common type of soft tissue injury, while the lower limb was the most common location of injury in rugby union players, and running was responsible for the highest injury incidence during non-contact events.


Discovery of Pancreatic Ductal Adenocarcinoma-Related Aberrant Glycosylations: A Multilateral Approach of Lectin Microarray-Based Tissue Glycomic Profiling With Public Transcriptomic Datasets.
Aberrant protein glycosylation is one of the most notable features in cancerous tissues, and thereby glycoproteins with disease-relevant glycosylation alterations are fascinating targets for the development of biomarkers and therapeutic agents. For this purpose, a reliable strategy is needed for the analysis of glycosylation alterations occurring on specific glycoproteins during the progression of cancer. Here, we propose a bilateral approach combining lectin microarray-based tissue glycomic profiling and database-derived transcriptomic datasets. First, lectin microarray was used to perform differential glycomic profiling of crude extracts derived from non-tumor and tumor regions of frozen tissue sections from pancreatic ductal adenocarcinoma (PDAC). This analysis revealed two notable tissue glycome alterations in PDAC samples: increases in sialylated glycans and bisecting N-acetylglucosamine and a decrease in ABO blood group antigens. To examine aberrations in the glycosylation machinery related to these glycomic alterations, we next employed public datasets of gene expression profiles in cancerous and normal pancreases provided by The Cancer Genome Atlas and the Genotype-Tissue Expression projects, respectively. In this analysis, glycosyltransferases responsible for the glycosylation alterations showed aberrant gene expression in the cancerous tissues, consistent with the tissue glycomic profiles. The correlated alterations in glycosyltransferase expression and tissue glycomics were then evaluated by differential glycan profiling of a membrane N-glycoprotein, basigin, expressed in tumor and non-tumor pancreatic cells. The focused differential glycomic profiling for endogenous basigin derived from non-tumor and cancerous regions of PDAC tissue sections demonstrated that PDAC-relevant glycan alterations of basigin closely reflected the notable features in the disease-specific alterations in the tissue glycomes. In conclusion, the present multi-omics strategy using public transcriptomic datasets and experimental glycomic profiling using a tiny amount of clinical specimens successfully demonstrated that basigin is a representative N-glycoprotein that reflects PDAC-related aberrant glycosylations. This study indicates the usefulness of large public data sets such as the gene expression profiles of glycosylation-related genes for evaluation of the highly sensitive tissue glycomic profiling results. This strategy is expected to be useful for the discovery of novel glyco-biomarkers and glyco-therapeutic targets.


Dynamics in inhomogeneous liquids and glasses via the test particle limit.
We show that one may view the self-part and the distinct-part of the van Hove dynamic correlation function of a simple fluid as the one-body density distributions of a binary mixture that evolve in time according to dynamical density functional theory. For a test case of soft-core Brownian particles the theory yields results for the van Hove function that agree quantitatively with those of our Brownian dynamics computer simulations. At sufficiently high densities the free energy landscape underlying the dynamics exhibits a barrier as a function of the mean particle displacement, shedding new light on the nature of glass formation. For hard spheres confined between parallel planar walls the barrier height oscillates in phase with the local density, implying that the mobility is maximal between layers, which should be experimentally observable in confined colloidal dispersions.


Targeted subsidy for malaria control with treated nets using a discount voucher system in Tanzania.
During the last decade insecticide-treated nets have become a key strategy for malaria control. Social marketing is an appealing tool for getting such nets to poor rural African communities who are most afflicted by malaria. This approach usually involves subsidized prices to make nets and insecticide more affordable and help establish a commercial market. We evaluated a voucher system for targeted subsidy of treated nets in young children and pregnant women in two rural districts of southern Tanzania. Qualitative work involved focus group discussions with community leaders, male and female parents of children under 5 years. In-depth interviews were held with maternal and child health clinic staff and retail agents. Quantitative data were collected through interviewing more than 750 mothers of children under 5 years during a cluster sample survey of child health. The voucher return rate was extremely high at 97% (7720/8000). However, 2 years after the start of the scheme awareness among target groups was only 43% (45/104), and only 12% of women (12/103; 95% CI 4-48%) had used a voucher towards the cost of a net. We found some evidence of increased voucher use among least poor households, compared with the poorest households. On the basis of these results we renewed our information, education and communication (IEC) campaign about vouchers. Discount vouchers are a feasible system for targeted subsidies, although a substantial amount of time and effort may be needed to achieve high awareness and uptake - by which we mean the proportion of eligible women who used the vouchers - among those targeted. Within a poor society, vouchers may not necessarily increase health equity unless they cover a high proportion of the total cost: since some cash is needed when using a voucher as part-payment, poorer women among the target group are likely to have lower uptake than richer women. The vouchers have two important additional functions: strengthening the role of public health services in the context of a social marketing programme and forming an IEC tool to demonstrate the group at most risk of severe malaria.


Peptide-based vaccines in the treatment of specific allergy.
The efficacy of conventional allergen-specific immunotherapy (SIT) for allergic conditions and venom hypersensitivity is well documented. However it's use is limited due allergic side effects including anaphylaxis and the difficulty of standardising proteins in complex allergenic mixtures. The aim of new therapeutic strategies is to circumvent these limitations and approaches include allergen non-specific therapy, such as anti-IgE and anti-cytokine therapy and other allergen specific techniques including the peptide based vaccines (PBV), modified allergens (allergoids) and DNA vaccines. PBV are small linear peptide fragments containing T cell epitopes which are designed to reduce the ability to cross link antigen-specific IgE. Studies in animal models have confirmed proof of principle demonstrating the induction of hyporesponsiveness using high doses of peptides. However, the principle limitation to clinical use of PBV is the polymorphism of HLA class II molecules. There are ongoing clinical studies using peptide-based vaccines for cat, bee and grass allergies--looking at both immunological mechanisms and clinical outcome measures. The mechanisms underlying the efficacy of PBV appear to be similar to those described for classical immunological tolerance. Thus, the peptides may induce anergy due to absence of co-stimulation, activation-induced cell death, a switch from a Th2 to a Th1 cytokine profile, the induction of regulatory T cells or combinations of these mechanisms. Successful immunotherapy, in bee sensitive individuals, is associated with the elaboration of IL-10. Clonal deletion is unlikely as an overall mechanism as there is evidence that the subsequent in vitro response to associated, non-injected, peptides can be suppressed. Mechanistic studies continue to provide insight into the mode of action of whole allergen and peptide-based immunotherapy. Clinical studies designed on the basis of these observations hold the promise of safer vaccines with improved efficacy. Whether this strategy can be used for allergy to complex allergen mixtures such as dust mites will need further evaluation.


Quality of life in stabilized outpatients with bipolar I disorder: Associations with resilience, internalized stigma, and residual symptoms.
Improving Quality of Life (QoL) is an important objective in the treatment of bipolar disorder. The aim of the current study was to examine to which extent resilience, internalized stigma, and psychopathology are correlated to QoL. We recruited 60 outpatients diagnosed with bipolar I disorder according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, symptoms were quantified by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) and internalized stigma by the Internalized Stigma of Mental Illness (ISMI) scale. In order to assess QoL and resilience, the Berliner Lebensqualitätsprofil (BELP) and the Resilience Scale (RS-25) were used in both patients and control subjects. Despite presenting with a very mild symptom level and relatively low internalized stigma, patients with bipolar I disorder indicated significantly lower QoL and resilience as compared to healthy control subjects. In patients, QoL correlated significantly with resilience, internalized stigma, and residual symptoms of depression. No significant correlations were observed between QoL and residual manic symptoms. The cross-sectional design and the relatively small sample size limit the generalizability of our results. Furthermore, levels of resilience and internalized stigma may change over the course of the illness and have different impacts on the long-term outcome of patients with bipolar disorder. Our results show that QoL of patients suffering from bipolar I disorder, even when only mildly ill, is strongly associated with the degree of resilience and internalized stigma, and that particularly residual depressive symptoms have a negative impact on QoL. In addition to drug treatment, psychotherapeutic approaches should be applied to strengthen resilience, to reduce internalized stigma, and, ultimately, to improve quality of life.


Circadian expression of the dnaK gene in the cyanobacterium Synechocystis sp. strain PCC 6803.
The expression of the dnaK gene in the cyanobacterium Synechocystis sp. strain PCC 6803 was continuously monitored as bioluminescence by an automated monitoring system, using the bacterial luciferase genes (luxAB) of Vibrio harveyi as a reporter of promoter activity. A dnaK-reporting bioluminescent Synechocystis strain was constructed by fusing a promoterless segment of the luxAB gene set downstream of the promoter region of the Synechocystis dnaK gene and introduction of this gene fusion into a BglII site downstream of the ndhB gene in the Synechocystis chromosome. Bioluminescence from this strain was continuously monitored and oscillated with a period of about 22 h for at least 5 days in continuous light. The phase of the rhythm was reset by the timing of the 12-h dark period administered prior to the continuous light. The period of the rhythm was temperature compensated between 25 and 35 degrees C. Thus, the bioluminescence rhythm satisfied the three criteria of circadian rhythms. Furthermore, the abundance of dnaK mRNA also oscillated with a period of about 1 day for at least 2 days in continuous light conditions, indicating circadian control of dnaK gene expression in Synechocystis sp. strain PCC 6803.


Challenges in pain assessment in cognitively intact and cognitively impaired older adults with cancer.
To describe approaches to pain assessment in cognitively intact and cognitively impaired older adults with cancer. MEDLINE literature search, personal reference collection, and clinical experience. A systematic and comprehensive pain assessment is the cornerstone of effective treatment strategies. Determining the effect of pain on older adults' ability to function is as important as rating pain intensity. Evidence-based recommendations exist to guide practice. The undertreatment of pain in older adults persists despite a plethora of published guidelines addressing pain assessment and management. Unrelieved pain affects recovery from illness and all aspects of life. Systematic and ongoing assessment is elementary to effective pain management, yet assessments frequently are neither completed nor documented. Because pain is subjective and individual responses to pain interventions vary widely and are unpredictable, assessment is vital to comprehensive pain care in all clinical settings. Reliable and validated pain assessment tools for cognitively intact and cognitively impaired older adults are available to guide practice. Pain assessment is a core competency for nurses in all clinical settings. Comprehensive, individualized, and ongoing assessment provides the information necessary so that clinicians can develop interventions to relieve patients' pain and improve their quality of life. Nurses have the knowledge, skills, and tools to adequately screen and comprehensively assess pain in older adult patients, including those with cognitive impairment. By using this knowledge, nurses can change systems and practices, have a significant effect on improving pain care, and increase quality of life and function of older adults with pain.